Ligand controlled highly regio- and enantioselective synthesis of α-acyloxyketones by palladium-catalyzed allylic alkylation of 1,2-enediol carbonates

Article abstract of DOI:10.1021/ja8038954

The palladium catalyzed decarboxylative asymmetric allylic alkylation of allyl 1,2-enediol carbonates 1 can decompose to either α-hydroxyketones 3 or α-hydroxyaldehydes 4. The product distribution is largely controlled by the ligand. Using L_naph

Full text of DOI:10.1021/ja8038954

Published on Web 08/19/2008
Ligand Controlled Highly Regio- and Enantioselective Synthesis of
r-Acyloxyketones by Palladium-Catalyzed Allylic Alkylation of 1,2-Enediol
Carbonates
Barry M. Trost,* Jiayi Xu, and Thomas Schmidt
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received May 23, 2008; E-mail: bmtrost@stanford.edu
Table 1. Selected Optimization Studiesa
R-Hydroxy carbonyl compounds represent a structural type of both
synthetic and biological importance. We previously noted that the enol
allyl carbonates of R-siloxycarbonyl compounds underwent smooth
palladium catalyzed decarboxylative asymmetric allylic alkylation
(AAA)1 to allylated R-siloxyaldehydes using a Pd complex bearing
the Lanth ligand regardless of the regioisomeric nature of the starting
entry
substrate (R)
ligand
solvent
yieldb
3/4c
ee of 3d
material (i.e., I or II in eq 1).2 The regioselectivity may be interpreted
as a faster equilibration between the Pd enolate A and B compared to
the rate of alkylation which occurs faster via B (i.e., k > k2 > k1).
However, if A and B exist as either tight ion-pairs or covalently bonded
enolates as we proposed before,1c the Pd catalyst should be involved
in both R migration and enolate alkylation steps. Thus, by tuning the
ligand and the potential migrating group, we envisioned that we could
change the reaction pattern in favor of the formation of R-hydroxy-
ketones III, which have attracted much attention because of their
versatile roles in organic synthesis.1k,3 Herein, we report our success
in the highly regio- and enantioselective synthesis of R-acyloxyketones
by such an approach.
1
2
3
4
5
6
7
8
1a (TBS)
1a
1a
1a
1a
1b (Ac)
1b
1b
1b
1b
Lanth
Lstd
Lstlb
PHOX
Lnaph
Lnaph
Lnaph
Lanth
Lstd
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DME
DME
DME
DME
DME
DME
DME
dioxane
DME
dioxane
95%
93%
93%
77%
91%
99%
99%
27%
93%
53%
46%
95%
99%
99%
79%
88%
1/33
2.7/1
2.8/1
1/4.2
17/1
49/1
49/1
3/2
-
77%
91%
-17%
85%
82%
90%
25%
79%
83%
-11%
74%
94%
-
9
25/1
7/1
10
11
12
13
14
15
16
Lstlb
1b
PHOX
Lnaph
Lnaph
Lnaph
Lnaph
PHOX
11/1
49/1
49/1
1/49
1/49
1/7.7
1c (Bz)
1d (Piv)
2a (TBS)
2d (Piv)
2a (TBS)
-
-18%
a Unless otherwise indicated, all reactions were performed on a 0.2
mmol scale at 0.1 M concentration at 23 °C for 16 h, using 2.5 mol %
Pd2(dba)3CHCl3 and 5.5 mol % ligand. b The yields were combined
isolated yields of 3 and 4. c The molar ratios of 3 and 4 were
determined by 1H NMR of the crude products. d The ee values were
determined by HPLC on a chiral stationary phase.
Initially we investigated the role of ligands by using carbonate 1a
(R ) tert-butyldimethylsilyl, TBS) as the substrate, which as we
reported previously, in the presence of Lanth decarboxylatively alkylated
to the corresponding siloxyaldehyde 4a with high regioselectivity
(Table 1, entry 1). PHOX ligands, which, similar to Lanth, have also
been successfully used to catalyze the decarboxylative AAA of enol
allyl carbonates, favored the formation of the aldehyde product in a
ratio of 4.2 to 1; however, the ee of 3a was much lower (17%, entry
was exclusively generated in the presence of Lnaph (entry 14 and 15).
This suggests that the equilibrium between A and B is slower than
the alkylation steps (k < k1, k2), in stark contrast to the reaction
catalyzed by Lanth. The same reaction catalyzed by PHOX ligand
(entry 16), however, gave a similar amount of aldehyde 4a (3a/4a )
1/7.7) as in the reaction of entry 4 (3a/4a ) 1/4.2), implying a faster
equilibrium and comparably slower alkylation (k > k1 ≈ k2).
4). In contrast to these results, varying our ligands to Lstd and Lstlb
,
slightly favored the formation of the ketone product (entry 2 and 3).
The best selectivity (3a/4a ) 17/1) was achieved by using Lnaph (entry
5). Replacement of OTBS with OAc almost completely suppressed
the formation of the aldehyde product (entry 6). Changing solvent from
dioxane to 1,2-dimethoxyethane (DME), kept the excellent regio-
selectivity but also improved the ee of 3b to 90% (entry 7).4 The ligand-
dependence of the product distribution of 1b was similar to that of
1a, although in all cases the ketone product was the major one (entry
8-11). Besides acetoxy other ester groups were also investigated, and
3d with R ) pivaloyl (Piv) had the highest ee value (94%, entry 13).
Starting from 2 (R ) TBS or Piv), which, after decarboxylation initially
generated the more stable Pd enolate B, only the aldehyde product
The scope of the reaction has been investigated and the results are
summarized in Table 2. Besides the aromatic ketones (entry 1-5),
enones such as 12b and 12d (entry 6 and 7), as well as aliphatic ketones
such as 14 and 16 (entry 8 and 9) can be obtained in good yields and
high ee’s. In general, pivolate protected R-hydroxyketones have
moderately higher ee’s than the corresponding acetate protected ones;
however, acetate is easier to be removed without loss of the enantio-
selectivity of the R-hydroxyketone. Substrates with a substituted allylic
moiety also reacted with full conversions, in some cases at slightly
warmer temperature (40 °C) (entry 10-12). The dr’s of the corre-
sponding products are over 95/5, and the ee values of the major
diastereomers are higher than that of 3b. These high dr’s are reflected
9
11852 J. AM. CHEM. SOC. 2008, 130, 11852–11853
10.1021/ja8038954 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction Scopea
equilibration is much slower with these Pd enolates and shows a
ligand dependence. In the case of using Lnaph as ligand it is slower
than the alkylation, so that no migration is observed even above
room temperature. This supports the concept that the decarboxyl-
ative AAA of ketones reacts through a tight ion pair or covalently
bonded Pd enolate intermediates.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Grant GM13598, for their generous support of our programs. J.
Xu has been supported by Abbott Laboratories Fellowships. We
thank Chirotech (now Dow) for their generous gifts of ligands and
Johnson Matthey for gifts of palladium salts.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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a All reactions were performed on a 0.2 mmol scale at 0.1 M in
DME at 23 °C for 16 h, using 2.5 mol % Pd2(dba)3CHCl3 and 5.5 mol
% Lnaph; the yields were isolated yields and ee values were determined
by chiral HPLC. b Reaction was performed at 4 °C. c Reaction was
performed at 40 °C. d Greater than 95/5 dr.
in the excellent ee’s of 29 and 30 by the hydrogenations of 20 and 22
respectively (eq 2). More interestingly, OR can be a functionalized
group as in 24, 26, and 28 (entry 13-15). Such functionality can be
useful in further structural elaboration as illustrated by the treatment
of 24 with Grubbs II catalyst to afford lactone 31 without any erosion
of enantioselectivity (eq 3).
In summary, the palladium-catalyzed decarboxylative AAA of
1,2-enediol carbonates can be precisely controlled by the selection
of the ligand to generate either regioisomer. Interestingly, although
acyl migration in sodium enolates is fast even at -78 °C,5 such
(4) The absolute configuration was assigned by the NMR study of the
corresponding O-methylmandelate ester. Trost, B. M.; Belletire, J. L.;
Godleski, S.; McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy,
M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986,
51, 2370.
(5) Observed in the preparation of substrates. See Supporting Information for
details.
JA8038954
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J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 11853